Abstract. In this SBIR Phase I application, our goal is to demonstrate proof of concept of our lead chelating agent as a potential therapeutic for the prevention of osteoporosis induced by aromatase inhibitor (AI) therapy in postmenopausal women with hormone-receptor-positive breast cancer. Although AI therapy shows great improvements in cancer-free and overall survival, its treated patients face a risk of osteoporosis, because AI inhibits estrogen generation. In fact, AI skeletal toxicity has become the most frequent reason for AI therapy discontinuation. Currently, there are very few therapeutic options for preventing AI-induced osteoporosis. Bisphosphonates and denosumab (two popular osteoporotic drugs) are protective; however both have an untreatable side-effect, osteonecrosis of the jaw, as well as other concerns regarding toxicity and inadequate therapeutic efficacy. Here, we hypothesize that AI-induced osteoporosis may be prevented by our chelating agent without adverse effects on AI actions; this agent is able to target new osteoporotic pathogens, hence having potential as a better alternative to current osteoporotic drugs for AI-treated breast cancer patients. This hypothesis is supported by our studies that show the ability of our chelating agent to prevent bone loss in ovariectomized (OVX) rats (a postmenopausal osteoporotic model due to estrogen deficiency). It is reasonable to exploit this finding toward the development of new drugs for treating AI-induced osteoporosis, due to the similarities of the OVX and AI mechanisms of actions in causing estrogen deficiency and consequent bone loss. Two US patents on this technology have been licensed to NanoMedic, a University of Utah (UU) startup company which has been broadening the technology application and seeking additional patent protection. Our aim is to synthesize the lead agent and define its efficacy for preventing osteopenic development in AI-treated OVX rats. Specifically: after synthesis, the agent will be evaluated in AI-treated OVX rats, and compared with rats that are sham-OVX, OVX, and OVX treated with AI or AI/bisphosphonate. A dose-response study will be conducted to further confirm the therapeutic efficacy. Collected bone samples (e.g., femur, tibia and vertebra) will be examined for treatment effectiveness using histomorphometric methods and various imaging technologies. Blood samples will also be tested for estrogen levels to determine whether the agent has any adverse effects on AI treatment, and for serum bone biomarkers in order to evaluate the agent's efficacy. All of these types of experimental procedures have been performed in our lab. To our best knowledge, our lab is the only one to develop a new kind of chelation therapeutic approach for AI-induced bone loss. Our team possesses multidisciplinary expertise in chelating drug discovery, bone biology, and bone therapeutic evaluation. We believe that this Phase I study will succeed, and lay the foundation for the following Phase II study - to fulfill an investigational new drug submission to the FDA. Ultimately, our development will bring new, effective osteoporotic adjuvant drugs to the global market.